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Regulating the Human HECT E3 Ligases

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Regulating the Human HECT E3 Ligases Cellular and Molecular Life Sciences (2018) 75:3121–3141 https://doi.org/10.1007/s00018-018-2848-2 Cellular andMolecular Life Sciences REVIEW Regulating the human HECT E3 ligases Jasper Sluimer1 · Ben Distel1,2 Received: 25 February 2018 / Revised: 23 May 2018 / Accepted: 28 May 2018 / Published online: 1 June 2018 © The Author(s) 2018 Abstract Ubiquitination, the covalent attachment of ubiquitin to proteins, by E3 ligases of the HECT (homologous to E6AP C ter- minus) family is critical in controlling diverse physiological pathways. Stringent control of HECT E3 ligase activity and substrate specifcity is essential for cellular health, whereas deregulation of HECT E3s plays a prominent role in disease. The cell employs a wide variety of regulatory mechanisms to control HECT E3 activity and substrate specifcity. Here, we summarize the current understanding of these regulatory mechanisms that control HECT E3 function. Substrate specifcity is generally determined by interactions of adaptor proteins with domains in the N-terminal extensions of HECT E3 ligases. These N-terminal domains have also been found to interact with the HECT domain, resulting in the formation of inhibi- tory conformations. In addition, catalytic activity of the HECT domain is commonly regulated at the level of E2 recruit- ment and through HECT E3 oligomerization. The previously mentioned regulatory mechanisms can be controlled through protein–protein interactions, post-translational modifcations, the binding of calcium ions, and more. Functional activity is determined not only by substrate recruitment and catalytic activity, but also by the type of ubiquitin polymers catalyzed to the substrate. While this is often determined by the specifc HECT member, recent studies demonstrate that HECT E3s can be modulated to alter the type of ubiquitin polymers they catalyze. Insight into these diverse regulatory mechanisms that control HECT E3 activity may open up new avenues for therapeutic strategies aimed at inhibition or enhancement of HECT E3 function in disease-related pathways. Keywords Ubiquitination · HECT E3 ligase · Substrate recruitment · Intramolecular interaction · Activity regulation · Oligomerization · Post-translational modifcation Introduction regulation and this makes them attractive targets for thera- peutic intervention [1–3]. Ubiquitination is a post-translational modifcation that is E3 ligases are commonly grouped into three classes: important for regulating protein function and degradation. really interesting new genes (RINGs), homologous to E6AP The ubiquitination cascade comprises the sequential actions C terminus (HECTs), and RING-between-RINGs (RBRs). of the ubiquitin-activating enzyme (E1), ubiquitin-conju- While the three classes of E3 ligases all catalyze covalent gating enzymes (E2s), and ubiquitin ligases (E3s) (Fig. 1). attachment of ubiquitin to usually a Lys residue in the target Within the ubiquitin cascade, the E3 ligases primarily deter- protein, they difer in structure and mechanisms (reviewed mine specifcity regarding selection of target proteins and in [4]). A notable distinction in the mechanism between ubiquitination sites. E3s are often focal points of cellular the classes is that RING E3s catalyze a direct transfer of ubiquitin from the E2 to the target protein, whereas transfer of ubiquitin by HECT E3s (and RBR ligases) involves and intermediate step where the ubiquitin is frst transferred from * Ben Distel the E2 to an active-site cysteine residue on the HECT E3 [email protected] ligase before it is conjugated to the target protein. Target 1 Department of Medical Biochemistry, Academic proteins can be modifed by a single ubiquitin moiety on Medical Center, University of Amsterdam, Amsterdam, one or multiple sites, giving rise to mono- and multi-mono- The Netherlands ubiquitinated proteins, respectively. In addition, a wide vari- 2 Department of Neuroscience, Erasmus Medical Center, ety of polyubiquitin chains can be formed on target proteins, Wijtemaweg 80, 3015 CN Rotterdam, The Netherlands Vol.:(0123456789)1 3 3122 J. Sluimer, B. Distel Fig. 1 The ubiquitination cascade. The initial step involves the ATP- cally bound to an active-site cysteine of the HECT domain before it dependent transfer of ubiquitin to an active-site cysteine residue on is attached to the target protein. Target proteins can be modifed by the E1 ubiquitin-activating enzyme. In the next step, the ubiquitin mono-, multi-mono-, or polyubiquitin. As ubiquitin has seven internal is transferred from the E1 to the E2 ubiquitin-conjugating enzyme. lysine residues and an N-terminal amino group, all of which can be Once the E2 is charged with ubiquitin, it can associate with the E3 to ubiquitinated, a wide variety of polyubiquitin chains can be formed prepare the ubiquitin transfer to the target protein. A RING-E3 will (not shown). Depending on the type of (poly)ubiquitin modifcation, mediate a direct transfer of ubiquitin from the E2 to the target protein. either the function/localization of the target protein is changed (“reg- The substrate ubiquitination by HECT E3s (and RBR ligases, not ulation”) or the target protein is sent for degradation by the 26S pro- shown) involves an additional step where the ubiquitin is frst chemi- teasome (“degradation”) in which the ubiquitin moieties can be linked through either syndrome which is caused by the loss of maternally inher- one of the seven internal Lys residues (Lys6, Lys11, Lys27, ited UBE3A [9, 10]. E6AP was discovered through its inter- Lys29, Lys33, Lys48, or Lys63) in ubiquitin or through its action with the human papillomavirus protein (HPV) E6, N-terminal amino group. The consequences for the modifed which hijacks the E3 ligase to ubiquitinate the p53 tumor target protein are determined by the type of (poly)ubiqui- suppressor as well as several other cellular proteins resulting tin modifcation it received. Ubiquitination can result in the in their degradation [11, 12]. In a non-infected cell p53 is change of function, localization or activity of the modifed not a target of E6AP, but the E6 protein alters the substrate protein, or control its degradation via the 26S proteasome specifcity of the E3 ligase to target and ubiquitinate p53 (reviewed in [5]). [7]. The interaction between the E6 protein and E6AP is one The identifcation of the E6AP protein transcribed from example of how a HECT E3 ligase is activated and altered the ubiquitin-protein ligase E3A (UBE3A) gene led to the to ubiquitinate a specifc substrate through binding of an discovery of the HECT-type E3 ligase family [6–8]. HECT adaptor protein. E3s are directly implicated in cancer, hypertension, neurode- The interaction with adaptor proteins, such as the inter- generative disorders, and other diseases, such as Angelman action of E6 with E6AP, can not only change the substrate 1 3 3123 Regulating the human HECT E3 ligases specifcity of HECT E3s but also alter the structure of HECT E3 ligases the ubiquitin polymers they conjugate to the substrates. Post-translational modifcations (PTMs) are also preva- HECT E3 ligases can be distinguished from other classes lent in the alteration of HECT E3 ligase functionality such of ubiquitin E3 ligases in that they have an active-site as phosphorylation and the attachment of ubiquitin-like cysteine that forms an intermediate thioester bond with modifers (UBLs) [13–15]. Various mechanisms other than ubiquitin before the ubiquitin is linked to its substrate PTMs and interactions with adaptor proteins also regulate [8, 18]. RING E3s do not have this catalytic activity, but HECT E3 ligases such as intramolecular interactions, oli- rather act as allosteric activators of E2s that mediate the gomerization, and recruitment of the E2 (Fig. 2). transfer of ubiquitin from E2 to substrate directly [19]. This review aims to give a comprehensive overview of This direct transfer of ubiquitin from the E2 means that the diferent mechanisms through which HECT E3 ligase the linkage type of the ubiquitin chains catalyzed by RING activities and substrate specifcities are regulated. The E3s is generally determined by the specifc E2 conjugat- structural aspects of these regulatory mechanisms have ing enzyme [20]. In contrast, HECT E3 ligases form an been very recently surveyed [16], while the pathophysi- E3 ~ Ub intermediate prior to the transfer of ubiquitin to ological aspects of HECT E3 ligases have been addressed the substrate, allowing them to override any linkage-type by Schefner and Kumar [17]. In addition to providing a preferences that an E2 conjugating enzyme may have [21]. clearer perspective of the regulation of HECT E3 ligases, Consistent with this, some HECT E3s appear to have a this overview could show us which aspects of research on general preference for catalyzing chains of specifc linkage HECT E3s have made good progress and which areas of types even when they cooperate with diferent E2s: E6AP research have lagged behind. Together, these insights may predominantly assembles Lys48-linked chains [21–23]; lead to suggestions for future research and pave the way for Rsp5 and NEDD4.1 assemble preferentially Lys63-linked new therapeutic strategies for many diseases. chains [21–23]; UBE3C promotes formation of Lys29- and Lys48-linked chains [22]; and recently it was shown that WWP1 assembles ubiquitin chains containing Lys63, Lys48, and Lys11 linkages [24]. For most other HECT E3s their linkage-type preferences, if any, remain to be discovered. Along with ubiquitin, HECT E3s are found in all eukaryotic organisms. HECT domain-like E3 proteins have also been found in pathogenic bacteria [25]. These bacteria presumably exploit the ubiquitin system of their host cells by injecting them with the respective HECT domain-like E3s [26]. Another characteristic of some HECT E3 ligases is that they are capable of catalyzing UBL proteins to their substrates such as NEDD8 (neural precursor cell expressed developmentally down-regulated protein 8) [14] and ISG15 (ubiquitin-like modifer IFN- stimulated gene 15) [27–29]. The HECT domain The HECT domain is an approximately 40 kDa domain positioned at the C-terminal of the E3 ligases that consists of two fexibly tethered lobes (the N- and C-lobes).
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